Project Summary/Abstract Drug discovery is an inherently risky endeavor and has proven to be especially so in Alzheimer?s disease (AD). Risk at project inception can be categorized as ?validation risk? (the likelihood that modulation of the target will have a favorable outcome in patients) or ?technical risk? (the likelihood that a tolerable molecule that modulates the target in patients can be discovered). The Open Drug Discovery Center for Alzheimer?s Disease (Open-AD) initiative will create a set of complementary bioinformatic, structural and pharmacologic tools (high-quality chemical probes) to evaluate a diverse set of AD hypotheses in an open discovery environment. Creation of high-quality chemical probes that are active in cellular and animal models of AD versus less explored targets can decrease the technical and validation risk inherent in discovery of new drugs for this disease. Scientists in the Med Chem Core have been successful in developing and sharing freely with the scientific community first-in-class chemical probes unburdened by intellectual property. We are committed to exploring our overarching hypothesis that open drug discovery will accelerate the development of AD medicines through robust and independent evaluation of a diverse set of untested AD therapeutic hypotheses utilizing the most impactful of all tools; a high-quality, cellular and in vivo active chemical probes. Aim 1. Portfolio creation: The Med Chem Core will work closely with the Bioinf and Struct Bio Cores to select a portfolio of novel AD related targets such that 6 targets enter the hit discovery phase each year. Targets will be vetted for the technical risk of probe discovery and prioritized for screening based upon this and the disease validation risk. Aim 2. Hit discovery: The Assay and Screen Core will take the lead on diversity-based HTS for hit discovery. The Med Chem Core will therefore focus on complementary, knowledge-based approaches, such as: virtual screening, focused screening using custom libraries, optimization of fragment-based hits discovered in the Struct Bio Core, structure-guided ligand design, and other rationale approaches. Aim 3. Hit to probe: The Med Chem Core will apply state-of-the-art medicinal chemistry strategies to iteratively design sets of drug-like analogues with physical-chemical properties consistent with CNS penetration. These will be assessed in a hierarchy of assays to address target affinity, selectivity, cellular activity, and in vitro ADME properties. As compounds achieve the desired activity in these assays, they will advance into in vivo assessment of plasma/brain PK and target engagement. Final probes will be extensively characterized to support their MOA and efficacy by the Assay and Screen Core in models of AD. The overall goal of the Med Chem Core is to deliver 3 cellular and 1-2 in vivo probes per year versus novel targets implicated in AD, which will be made freely available to the scientific community. ! 1!